Hydroxyquinoline amines, and method of enhancing memory in mammals

ABSTRACT

There are disclosed novel compounds of the formula ##STR1## where X is hydrogen, loweralkyl, loweralkoxy, hydroxy, halogen, nitro or trifluoromethyl; R 1  is hydrogen or loweralkyl; R 2  is hydrogen, loweralkyl, arylloweralkyl or --(CH 2 ) m  R 7  wherein m is 1, 2 or 3 and R 7  is cyano or amino; R 3  and R 4  are independently hydrogen or loweralkyl; R 5  and R 6  are independently hydrogen or loweralkyl, or R 5  +R 6  taken together with the carbon atom to which they are attached constitute a cyclobutane, cyclopentane, cyclohexane, cycloheptane, pyrrolidine, piperidine, morpholine or thiomorpholine ring, or R 5  is hydrogen and R 6  is aryl or --CH 2  OR 8  wherein R 8  is hydrogen, loweralkyl or loweralkylcarbonyl, which are useful for enhancing memory.

This is a division, of application Ser. No. 072,832, filed July 13,1987, now U.S. Pat. No. 4,743,601.

The present invention relates to novel compounds of the formula,##STR2## where X is hydrogen, loweralkyl, loweralkoxy, hydroxy, halogennitro or trifluoromethyl; R₁ is hydrogen or loweralkyl; R₂ is hydrogen,loweralkyl, arylloweralkyl or --(CH₂)_(m) R₇ wherein m is 1, 2 or 3 andR₇ is cyano or amino; R₃ and R₄ are independently hydrogen orloweralkyl; R₅ and R₆ are independently hydrogen or loweralkyl, or R₅+R₆ taken together with the carbon atom to which they are attachedconstitute a cyclobutane, cyclopentane, cyclohexane, cycloheptane,pyrrolidine, piperidine, morpholine or thiomorpholine ring, or R₅ ishydrogen and R₆ is aryl or --CH₂ OR₈ wherein R₈ is hydrogen, loweralkylor loweralkylcarbonyl, which are useful for enhancing memory; topharmaceutical compositions comprising an effective memory enhancingamount of such a compound; and to a method of treating a patient in needof memory enhancement which comprises administration of an effectiveamount of such a compound.

This invention also relates to novel compounds of the formula, ##STR3##where X, R₁ and R₃ through R₆ are as defined earlier and R₉ is hydrogenor bromine (with the proviso that when R₁ =R₃ =R₄ =R₅ =R₉ =H, X is not7-chloro) which are also useful for enhancing memory and for preparingcompounds of formula I.

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo optical, and geometricalisomers thereof where such isomers exist, as well as pharmaceuticallyacceptable acid addition salts thereof and solvates thereof such as forinstance hydrates.

The following general rules of terminology shall apply throughout thespecification and the appended claims.

Unless otherwise stated or indicated, the term loweralkyl denotes astraight or branched alkyl group having from 1 to 6 carbon atoms.Examples of said loweralkyl group include methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- andbranched-chain pentyl and hexyl

Unless otherwise stated or indicated, the term loweralkoxy denotes astraight or branched alkoxy group having from 1 to 6 carbon atoms.Examples of said loweralkoxy include methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight-and branched-chain pentoxy and hexoxy

Unless otherwise stated or indicated, the term halogen shall meanfluorine, chlorine, bromine or iodine.

Unless otherwise stated or indicated, the term aryl shall mean a phenylgroup having 0, 1, 2 or 3 substituents each of which being independentlyloweralkyl, loweralkoxy, halogen or CF₃, and the term diaryl shall meantwo such aryl groups each of which being independent of the other.

The compounds of this invention are prepared by following one or more ofthe steps described below. Throughout the description of the syntheticsteps, the definitions of X and R₁ through R₉ are as given above unlessotherwise stated or indicated.

STEP A

A compound of formula III is reacted with a primary amine of formula IVto afford a compound of formula V. ##STR4##

This reaction is typically conducted in a suitable solvent, forinstance, a polar solvent such as butanol, 2-ethoxyethanol or the likeand by stirring the reaction mixture at a temperature of about 100°-180°C. Reflux condition is preferred. Optionally, triethylamine may be addedto the reaction mixture in order to facilitate the reaction Presence ofsolvent is not essential.

Alternatively to the above, the following two steps may be used toobtain compound V.

STEP B

A compound of formula VI is reacted with compound IV in substantiallythe same manner as in STEP A to afford compound of formula VII. ##STR5##

STEP C

Compound VII is reacted with bromine to afford compound V.

    (VII)+Br.sub.2 →(V)

This reaction is typically conducted at room temperature in the presenceof a suitable solvent such as acetic acid.

STEP D

Sometimes, it is convenient to obtain a compound of formula Va from thecorresponding chloro compound of formula Vb by use of hydrogenolysis.##STR6##

This hydrogenolysis is typically conducted in the presence of a suitablenoble metal catalyst such as palladium on carbon and a suitable reactionmedium such as methanol. It is preferable to add small amounts of aceticacid and sodium acetate to the reaction system. The reaction istypically conducted at room temperature while the mixture is beingshaken.

STEP E

Compound V obtained from one of the foregoing steps is cyclized toafford a compound of formula VIII. ##STR7##

This cyclization is typically conducted in the presence of a suitablesolvent such as dimethylformamide and a strong base such as potassiumtertiary butoxide or sodium hydride and by stirring the reaction mixtureat a temperature of about 70°-150° C.

STEP F

Compound VIII is reacted with a loweralkyl chloride or arylloweralkylchloride of the formula R₁₀ --Cl where R₁₀ is loweralkyl orarylloweralkyl in a routine manner known to the art to obtain a compoundof formula IX. ##STR8##

STEP G

Compound VIII is reacted with a compound of formula X in a routinemanner known to the art to obtain a compound of formula XI. ##STR9##

Alternatively to the above, where m is 2 in formula XI, the desiredproduct can also be obtained by reacting compound VIII withacrylonitrile rather than NCCH₂ CH₂ Br in a routine manner known to theart.

STEP H

Compound XII is reduced in a routine manner known to the art to obtain acompound of formula XII. ##STR10##

The compounds of formula I and II of the present invention are useful inthe treatment of various memory dysfunctions characterized by decreasedcholinergic function, such as Alzheimer's disease.

This utility is demonstrated by the ability of these compounds torestore cholinergically deficient memory in the Dark Avoidance Assay,where they are in general active over a broader dose range thanheretofore known compounds, a distinct therapeutic advantage.

Dark Avoidance Assay

In this assay mice are tested for their ability to remember anunpleasant stimulus for a period of 24 hours. A mouse is placed in achamber that contains a dark compartment; a strong incandescent lightdrives it to the dark compartment, where an electric shock isadministered through metal plates on the floor. The animal is removedfrom the testing apparatus and tested again, 24 hours later, for theablity to remember the electric shock.

If scopolamine, an anticholinergic agent that is known to cause memoryimpairment, is administered before an animals' initial exposure to thetest chamber, the animal re-enters the dark compartment shortly afterbeing placed in the test chamber 24 hours later. This effect ofscopolamine is blocked by an active test compound, resulting in greaterinterval before re-entry into the dark compartment.

The results for an active compound are expressed as the percent of agroup of animals in which the effect of scopolamine is blocked, asmanifested by an increased interval between being placed in the testchamber and re-entering the dark compartment. Results for some of thecompounds of this invention are presented in Table 1.

                  TABLE 1                                                         ______________________________________                                                                % of Animals                                                                  With Scopolamine                                                  Dose (mg/kg of                                                                            Induced Memory                                                    Body Weight), s.c.                                                                        Deficit Reversed                                      ______________________________________                                        Compound                                                                      1,2-dihydro-3-methyl-3H-                                                                    0.16          27%                                               1,4-oxazino[2,3-c]                                                                          2.50          47%                                               quinoline                                                                     7-chloro-N-(2-hydroxy-                                                                      1.25          27%                                               propyl-4-quinolinamine                                                                      2.50          47%                                               8-chloro-1,2-dihydro-                                                                       0.16          21%                                               2-methyl-3H-1,4-oxazino-                                                      [2,3-c]quinoline                                                              3-bromo-N-(2,3-                                                                             0.31          40%                                               dihydroxypropyl)-2-                                                           methyl-4-quinolinamine                                                        (reference compound)                                                          Physostigmine 0.31          20%                                               ______________________________________                                    

Effective quantities of the compounds of the invention may beadministered to a patient by any of the various methods, for example,orally as in capsules or tablets, parenterally in the form of sterilesolutions or suspensions, and in some case intravenously in the form ofsterile solutions. The free base final products, while effectivethemselves, may be formulated and administered in the form of theirpharmaceutically acceptable acid addition salts for purposes ofstablity, convenience of crystallization, increased solubility and thelike.

Acids useful for preparing the pharmaceutically acceptable acid additionsalts of the invention include inorganic acids such as hydrochloric,hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as wellas organic acids such as tartaric, citric, acetic, succinic, malic,fumaric and oxalic acids.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an ediblecarrier, or they may be enclosed in gelatin capsules, or they may becompressed into tablets. For the purposes of oral therapeuticadministration, the active compounds of the invention may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gum and thelike. These preparations should contain at least 0.5% of activecompound, but may be varied depending upon the particular form and mayconveniently be between 4% to about 70% of the weight of the unit. Theamount of active compound in such compositions is such that a suitabledosage will be obtained Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 milligrams of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as micro-crystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, cornstarch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin may be added or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit form may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus tablets or pills may be coated with sugar,shellac, or other enteric coating agents A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes, coloring and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of activecompound, but may be varied between 0.5 and about 30% of the weightthereof. The amount of active compound in such compositions is such thata suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 milligrams of activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphate and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in disposable syringes or multiple dose vials made ofglass or plastic.

Examples of compounds according to this invention include:

N-(2-hydroxyethyl)-4-quinolinamine;

7-chloro-N-(2-hydroxy-1-methylethyl)-4-quinolinamine;

7-chloro-N-(2-hydroxy-1-phenylethyl)-4-quinolinamine;

7-chloro-N-(2-hydroxypropyl)-4-quinolinamine;

N-(2,3-dihydroxypropyl)-2-methyl-4-quinolinamine;

7-chloro-N-(2-hydroxy-2-phenylethyl)-4-quinolinamine;

N-(2-hydroxy-2-phenylethyl)-4-quinolinamine;

7-chloro-N-[(1-hydroxycyclohexyl)methyl]-4-quinolinamine;

3-bromo-N-(2-hydroxyethyl)-4-quinolinamine;

3-bromo-N-(2-hydroxyethyl)-2-methyl-4-quinolinamine;

3-bromo-7-chloro-N-(2-hydroxyethyl)-4-quinolinamine;

3-bromo-N-(2-hydroxyethyl)-7-trifluoromethyl-4-quinolinamine;

3-bromo-7-chloro-N-(2-hydroxy-1-methylethyl)-4-quinolinamine;

3-bromo-N-(2-hydroxypropyl)-4-quinolinamine;

3-bromo-N-(2-hydroxypropyl)-2-methyl-4-quinolinamine;

3-bromo-7-chloro-N-(2-hydroxypropyl)-4-quinolinamine;

3-bromo-N-(2,3-dihydroxypropyl)-2-methyl-4-quinolinamine;

3-bromo-N-(2-hydroxy-2-phenylethyl)-4-quinolinamine;

3-bromo-N-(1-hydroxycyclohexylmethyl)-4-quinolinamine;

3-bromo-7-chloro-N-(1-hydroxycyclohexylmethyl)-4-quinolinamine;

1,2-dihydro-3H-1,4-oxazino[2,3-c]quinoline;

1,2-dihydro-5-methyl-3H-1,4-oxazino[2,3-c]quinoline;

8-chloro-1,2-dihydro-3H-1,4-oxazino[2,3-c]quinoline;

8-chloro-1,2-dihydro-2-methyl-3H-1,4-oxazino[2,3-c]quinoline;

1,2-dihydro-3-methyl-3H-1,4-oxazino[2,3-c]quinoline;

1,2-dihydro-3,5-dimethyl-3H-1,4-oxazino[2,3-c]quinoline;

8-chloro-1,2-dihydro-3-methyl-3H-1,4-oxazino[2,3-c]quinoline;

1,2-dihydro-3-hydroxymethyl-3H-5-methyl-1,4-oxazino[2,3-c]-quinoline;

1,2-dihydro-3-phenyl-3H-1,4-oxazino[2,3-d]quinoline;

spiro[cyclohexane-1,3'-[3H][1,4]oxazino[2,3-c]quinoline];

8'-chloro-spiro[cyclohexane-1,3'-[3H][1,4]oxazino[2,3-c]quinoline; and

1-(2-cyanoethyl)-1,2-dihydro-3H-1,4-oxazino[2,3-c]quinoline;

The following examples are presented in order to illustrate thisinvention.

EXAMPLE 1 N-(2-hydroxyethyl)-4-quinolinamine

A slurry of 0.86 g of palladium on carbon in isopropanol was pipettedinto a Parr shaker and to this was added a solution of 10 g of7-chloro-N-(2-hydroxyethyl)-4-quinolinamine and 6.1 g of sodium acetatein 260 ml of methanol and 7 ml of acetic acid. The mixture washydrogenated at 51 psi (pounds per square inch) until no furtherreaction was observed. Upon filtration through celite and evaporation ofsolvents an oil resulted which was dissolved in water and basified withsodium hydroxide. A solid resulted which was recrystallized fromisopropanol to give 8.5 g of purified compound with a melting point of152°-154° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.11 H.sub.12 N.sub.2 O:                                                    70.19% C 6.43% H  14.89% N                                   Found:           69.63% C 6.48% H  14.66% N                                   ______________________________________                                    

EXAMPLE 2 7-Chloro-N-(2-hydroxy-1-methylethyl)-4-quinolinamine

A mixture of 20 g of 4,7-dichloroquinoline and 16 g of2-amino-1-propanol in 60 ml of butanol was stirred at reflux. Thereaction was complete after three days of stirring and the vessel wasallowed to cool to room temperature. Water was added to the mixture andextraction was conducted with dichloromethane. Drying over anhydrousmagnesium sulfate and evaporation of solvents resulted in 17 g of solidwhich was triturated with ether. Recrystallization from ethanol/acetonegave 16 g of crystalline solid with a melting point of 210°-212° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.12 H.sub.13 ClN.sub.2 O:                                                  60.89% C 5.53% H  11.84% N                                   Found:           60.72% C 5.71% H  11.72% N                                   ______________________________________                                    

EXAMPLE 3 7-Choro-N-(2-hydroxy-1-phenylethyl)-4-quinolinamine

A mixture of 20 g of 4,7-dichloroquinoline and 14 g of D-(-)-phenylglycinol in 60 ml of butanol and 17 ml of triethylamine wasstirred at reflux. The reaction was complete after two days of stirringand the vessel was allowed to cool to room temperature. The mixture wasdiluted with 75 ml of water and extracted with dichloromethane (3×100ml). Drying over anhydrous magnesium sulfate and evaporation of solventsresulted in an oil which crystallized upon standing. The solid waspurified by HPLC using 16:1 dichloromethane/methanol as the eluent.Recrystallization from ethanol/acetone gave 18 g of solid with a meltingpoint of 220°-221° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.17 H.sub.15 ClN.sub.2 O:                                                  68.34% C 5.06% H  9.38% N                                    Found:           68.44% C 5.20% H  9.29% N                                    ______________________________________                                    

EXAMPLE 4 7-Chloro-N-(2-hydroxypropyl)-4-quinolinamine

A mixture of 20 g of 4,7-dichloroquinoline and 16 g of1-amino-2-propanol in 60 ml of butanol was stirred at reflux until thereaction was complete (6 hours) The reaction mixture was cooled down toroom temperature and diluted with water. The organics were exracted intodichloromethane (3×300 ml). Drying over anhydrous magnesium sulfate andevaporation of solvents resulted in an oil which crystallized uponstanding. The crystals were isolated by filtration and washed with etherto yield a solid which was recrystallized from isopropanol The resultantcrystals had a melting point of 168°-169.5° C. and the yield was 15 g.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.12 H.sub.13 ClN.sub.2 O:                                                  60.89% C 5.53% H  11.84% N                                   Found:           60.66% C 5.39% H  11.73% N                                   ______________________________________                                    

EXAMPLE 5 N-(2,3-dihydroxypropyl)-2-methyl-4-quinolinamine

A mixture of 4-chloro-2-methylquinoline (50 g) and3-amino-1,2-propandiol (51 g) was heated at 160° C. for 1 hour. Themixture while still hot was poured into 700 ml of water. The mixture wassaturated with potassium carbonate and cooled in an ice bath, whereuponthe product crystallized. It was filtered and recrystallized fromethanol. The yield was 55 g, mp 167°-168° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.13 H.sub.16 N.sub.2 O.sub.2 :                                             67.22% C 6.94% H  12.06% N                                   Found:           67.08% C 7.16% H  12.07% N                                   ______________________________________                                    

EXAMPLE 6 7-Chloro-N-(2-hydroxy-2-phenylethyl)-4-quinolinamine

A solution of 4,7-dichloroquinoline (19.8 g), 2-amino-1-phenylethanol(13.7 g) and 20 ml of triethylamine (14.5 g) in 10 ml of ethoxyethanolwas heated at 130° C. overnight. The mixture was poured into 600 ml ofwater and the solid product was collected by filtration recrystallizedfrom ethoxyethanol and washed with ethanol. The yield was 16 g, mp221°-222° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.17 H.sub.15 ClN.sub.2 O:                                                  68.34% C 5.03% H  9.38% N                                    Found:           68.33% C 4.98% H  9.40% N                                    ______________________________________                                    

EXAMPLE 7 N-(2-hydroxy-2-phenylethyl)-4-quinolinamine

A mixture of 7-chloro-N-(2-hydroxy-2-phenylethyl)-4-quinolinamine (10g), 0.8 g of palladium on powdered charcoal (10%), 5 ml of acetic acid,7 g of sodium acetate 3H₂ O and 200 ml of methanol was hydrogenated atroom temperature with shaking at 30-50 psi until completion of hydrogenuptake. The catalyst was filtered and the solvent evaporated. The oilresidue was dissolved in 20 ml of water and the solution made alkaline(pH=10) with and NaOH solution. The crystalline compound was filteredand recrystallized from isopropanol. The yield was 7.5 g, mp 289°-290°C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.17 H.sub.16 N.sub.2 O:                                                    77.27% C 6.06% H  10.61% N                                   Found:           77.03% C 6.05% H  10.59% N                                   ______________________________________                                    

EXAMPLE 8 7-Chloro-N-[(1-hydroxycyclohexyl)methyl]-4-quinolinamine

A solution of 20 g of 4,7-dichloroquinoline 20 g of1-aminomethyl-1-cyclohexanol hydrochloride and 3 equivalents oftriethylamine in 80 ml of 2-ethoxyethanol was stirred at reflux untilthe reaction was complete. The reaction was complete after 16 hours, andupon dilution of the reaction mixture with water (300 ml), a solidprecipitated out which was isolated by filtration. Recrystallizationfrom ethanol gave 16 g of crystalline solid with a melting point of205°-207° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.16 H.sub.19 ClN.sub.2 O:                                                  66.08% C 6.59% H  9.64% N                                    Found:           66.35% C 6.61% H  9.75% N                                    ______________________________________                                    

EXAMPLE 9 3-Bromo-N-(2-hydroxyethyl)-4-quinolinamine

A mixture of 9.1 g of 3-bromo-4-chloro-quinoline and 2.0 g ofethanolamine was heated at 150° C. for 30 minutes. The reaction mixturewas cooled, 60 ml of water was added and the precipitate was collectedby filtration and recrystallized from isopropanol. The yield was 9.5 g,mp 163°-165° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.11 H.sub.11 BrN.sub.2 O:                                                  49.44% C 4.12% H  10.49% N                                   Found:           49.31% C 4.19% H  10.32% N                                   ______________________________________                                    

EXAMPLE 10 3-Bromo-N-(2-hydroxyethyl)-2-methyl-4-quinolinamine

Bromine (15.6 g) was added dropwise to a solution ofN-(2-hydroxyetyl)-2-methyl-4-quinolinamine (26 g) in 400 ml of aceticacid. A solid separated which after one hour of stirring was filteredand dissolved in 400 ml of water. The free base was precipitated byadding 20% KOH solution until pH became 10. The solid was filtered andrecrystallized from isopropanol. The yield was 14.5 g, mp 154°-155° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.12 H.sub.13 BrN.sub.2 O:                                                  51.26% C 4.66% H   9.97% N                                   Found:           51.17% C 4.75% H  10.04% N                                   ______________________________________                                    

EXAMPLE 11 3-Bromo-7-chloro-N-(2-hydroxyethyl)-4-quinolinamine

Bromine (4.3 g) was added dropwise to a solution of7-chloro-N-(2-hydroxyethyl)-4-quinolinamine (6 g) in 60 ml of aceticacid. The mixture was stirred overnight and the solid separated byfiltration. This solid was dispensed in 100 ml of water and the mixturemade alkaline (pH=8) with a sodium bicarbonate solution. After two hoursof stirring, the product was filtered and recrystallized twice fromisopropanol and from ethanol. The yield was 3.5 g, mp 169°-170° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.11 H.sub.10 BrClN.sub.2 O:                                                 43.78% C 3.32% H  9.29% N                                   Found:            43.44% C 3.24% H  9.10% N                                   ______________________________________                                    

EXAMPLE 12 3-Bromo-N-(2-hydroxyethyl)-7-trifluoromethyl-4-quinolinamine

A solution of 12.4 g of 3-bromo-4-chloro-7-trifluoromethylquinoline and6.1 g of 2-aminoethanol in 30 ml of isopropanol was heated at reflux for4 hours. The mixture was cooled and diluted with 150 ml of water and thesolid was collected and recrystallized from isopropanol. The yield was8.2 g, mp 140°-141° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.12 H.sub.10 BrF.sub.3 N.sub.2 O:                                           43.00% C 2.99% H  8.36% N                                   Found:            42.94% C 3.07% H  8.32% N                                   ______________________________________                                    

EXAMPLE 13 3-Bromo-7-chloro-N-(2-hydroxy-1-methylethyl)-4-quinolinamine

A mixture of 12 g of 7-chloro-N-(2-hydroxy-1-methylethyl)4-quinolinamineand 112 ml of acetic acid was stirred at room temperature and to it 8 gof bromine was added dropwise over a thirty minute period. The productprecipitated from the solution as the hydrobromide salt and it wasisolated by filtration, dissolved in water and basified with sodiumhydroxide. The free base was extracted into dichloromethane andevaporation of solvents resulted in a solid which was purified by HPLCusing 95:5 dichloromethane/methanol as the eluent. Recrystallizationfrom isopropanol yielded 9 g of crystalline solid with a melting pointof 145°-147° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.12 H.sub.12 BrClN.sub.2 O:                                                 45.67% C 3.83% H  8.88% N                                   Found:            45.77% C 3.82% H  8.81% N                                   ______________________________________                                    

EXAMPLE 14 3-Bromo-N-(2-hydroxypropyl)-4-quinolinamine

A mixture of 3 g of 3-bromo-4-chloro-quinoline and 10 g ofaminopropanol-2 was heated to 150° C. for 20 minutes. The mixture wascooled and poured into 120 ml of water and the product was extractedwith 100 ml of ether. The ether layer was dried over sodium sulfate, thesolvent removed by evaporation and the residue recrystallized fromether/hexane. The yield was 2.6 g, mp 82°-83° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.12 H.sub.13 BrN.sub.2 O:                                                  51.25% C 4.63% H  9.96% N                                    Found:           50.85% C 4.51% H  9.80% N                                    ______________________________________                                    

EXAMPLE 15 3-Bromo-N-(2-hydroxypropyl)-2-methyl-4-quinolinamine

Bromine (32 g) was added dropwise to a solution of 44 g ofN-(2-hydroxypropyl)-2-methyl-4-quinolinamine in 600 ml of acetic acid.The solution was stirred for 1 hour and the HBr salt was filtered andwashed with a small amount of acetic acid. It was then dissolved in 500ml of water and an aqueous KOH solution was added, whereupon the freebase precipitated. It was filtered and recrystallized from isopropanol.The yield was 22 g, mp 147°-149° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.13 H.sub.15 BrN.sub.2 O:                                                  52.89% C 5.12% H  9.49% N                                    Found:           52.74% C 5.14% H  9.35% N                                    ______________________________________                                    

EXAMPLE 16 3-Bromo-7-chloro-N-(2-hydroxypropyl)-4-quinolinamine

A mixture of 12 g of 7-chloro-N-(2-hydroxypropyl)-4-quinolinamine in 112ml of acetic acid was stirred at room temperature and to it 8 g ofbromine was added dropwise over a thirty minute period. After 1.5 hours,a solid formed which was isolated by filtration, dissolved in water andbasified with sodium hydroxide, whereupon a solid formed which wascollected by filtration. Recrystallization from ethanol yielded 8 g ofsolid with a melting point of 161°-163° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.12 H.sub.12 BrClN.sub.2 O:                                                 45.67% C 3.83% H  8.88% N                                   Found:            45.27% C 3.74% H  8.76% N                                   ______________________________________                                    

EXAMPLE 17 3-Bromo-N-(2,3-dihydroxypropyl)-2-methyl-4-quinolinamine

Bromine (33.7 g) was added dropwise to a solution of 49 g ofN-(2,3-dihydroxypropyl)-2-methyl-4-quinolinamine in 600 ml of aceticacid. After two hours of stirring, the resultant oil was separated bydecantation, dissolved in 500 ml of water and the mixture made alkaline(pH=10) with potassium carbonate. The resultant free base solid wasfiltered and recrystallized from ethanol. The yield was 33 g, mp140°-141° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.13 H.sub.15 BrN.sub.2 O.sub.2 :                                            50.17% C 4.86% H  9.00% N                                   Found:            49.86% C 4.91% H  8.85% N                                   ______________________________________                                    

EXAMPLE 18 3-Bromo-N-(2-hydroxy-2-phenylethyl)-4-quinolinamine

A solution of 4 g of 3-bromo-4-chloro-quinoline and 6 g of2-hydroxy-2-phenyl-ethylamine was heated at 150° C. for 3 hours in 10 mlof ethoxyethanol. The mixture was cooled and poured into 150 ml ofwater. The product was extracted with two 50 ml portions of ether. Theether layer was dried over sodium sulfate, the solvent was evaporatedand the residue was recrystallized from isopropanol. The yield was 3.0g, mp 131°-132° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.17 H.sub.15 BrN.sub.2 O:                                                   59.48% C 4.37% H  8.16% N                                   Found:            59.04% C 4.34% H  8.01% N                                   ______________________________________                                    

EXAMPLE 19 3-Bromo-N-(1-hydroxycyclohexylmethyl)-4-quinolinamine

A mixture of 3-bromo-4-chloroquinoline (12.1 g),1-aminomethyl-1-cyclohexanol HCl (8.3 g), triethylamine (7.2 g) and 30ml of ethoxyethanol was stirred at 120° C. for 5 hours and poured into250 ml of ice water. The solid was filtered and recrystallized fromacetone. The yield was 6.5 g, mp 130°-132° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.16 H.sub.19 BrN.sub.2 O:                                                   57.33% C 5.67% H  8.36% N                                   Found:            56.97% C 5.67% H  8.17% N                                   ______________________________________                                    

EXAMPLE 203-Bromo-7-chloro-N-(1-hydroxycyclohexylmethyl)-4-quinolinamine

A solution of 11.2 g of7-chloro-N-(1-hydroxycyclohexylmethyl)-4-quinolinamine in 130 ml ofglacial acetic acid was stirred at room temperature and 6.15 g ofbromine was added dropwise. The product precipitated from the solutionas the hydrobromide salt and was isolated by filtration. The solid wasthen suspended in water and basified with sodium hydroxide. After twohours of stirring, the solid was collected by filtration. By combustionanalysis, the product proved to be a hemi-hydrobromide salt, andtherefore it was necessary to dissolve the solid in methanol and 1equivalent of trietylamine with heating. A solid resulted which wasrecrystallized from ethanol to give 7 g of crystalline solid withmelting point of 151°-154° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.16 H.sub.18 BrClN.sub.2 O:                                                 51.98% C 4.91% H  7.56% N                                   Found:            51.70% C 4.98% H  7.36% N                                   ______________________________________                                    

EXAMPLE 21 1,2-Dihydro-3H-1,4-oxazino[2,3-c]quinoline

A mixture of 8.0 g of 3-bromo-N-(2-hydroxyethyl)-4-quinolinamine and 4 gof potassium-tert-butoxide in 220 ml of dimethylformamide was heated atreflux for 3 hours. The reaction mixture was cooled to room temperatureand diluted with 200 ml of water and the product was extracted with 4portions of 50 ml of dichloromethane (DCM). The DCM solution was driedover sodium sulfate and concentrated. The oily residue was dissolved in150 ml of ethanol. To this solution 5 ml of concentrated HCl was added,the HCl salt was separated by filtration and recrystallized fromethanol. This crystalline material was dissolved in 75 ml of water andthe solution made alkaline (pH=8) with a sodium bicarbonate solution.The free base was filtered and dried in vacuo to yield 1.3 g of whitesolid, mp 175°-176° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.11 H.sub.10 N.sub.2 O:                                                   70.97% C 5.38% H    15.05% N                                  Found:          70.40% C 5.21% H    14.84% N                                  ______________________________________                                    

EXAMPLE 22 1,2-Dihydro-5-methyl-3H-1,4-oxazino[2,3-c]quinoline

A mixture of 3-bromo-N-(2-hydroxyethyl)-2-methyl-4-quinolinamine (11.5g), potassium-tert-butoxide (3.7 g) and 100 ml of dimethylformamide(DMF) was stirred at 80° C. for 3 hours. The mixture was cooled anddiluted with 600 ml of water and thereafter kept in a refrigerator for 2days. The resultant solid was filtered and recrystallized fromisopropanol. The yield was 3.3 g, mp 203°-204° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.12 H.sub.12 N.sub.2 O:                                                   71.97% C 6.04% H    13.99% N                                  Found:          71.49% C 6.20% H    13.78% N                                  ______________________________________                                    

EXAMPLE 23 8-Chloro-1,2-dihydro-3H-1,4-oxazino[2,3-c]quinoline

Sodium hydride (obtained from 3 g of 50% suspension in mineral oil) wasadded to a solution of3-bromo-7-chloro-N-(2-hydroxyethyl)-4-quinolinamine (15 g) in 30 ml ofDMF and the mixture stirred at 80°-90° C. for 2 hours. After cooling, itwas diluted with 300 ml of water and the product extracted with ethylacetate. The extract was dried over sodium sulfate, the solvent wasevaporated and the oily residue purified by high pressure liquidchromatography (HPLC) (hexane:ethyl acetate=1:1). The desired fractionswere combined, concentrated and recrystallized from isopropanol. Theyield was 2.0 g, mp 219°-220° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.11 H.sub.9 ClN.sub.2 O:                                                   59.86% C 4.08% H   12.70% N                                  Found:           59.61% C 4.10% H   12.48% N                                  ______________________________________                                    

EXAMPLE 24 8-Chloro-1,2-dihydro-2-methyl-3H-1,4-oxazino[2,3-c]quinoline

A solution of 10 g of3-bromo-7-chloro-N-(2-hydroxy-1-methylethyl)-4-quinolinamine in 28 ml ofDMF was stirred and to it was added 4.3 g of potassium-t-butoxide. Themixture was stirred at 120°-140° C. for 2 hours and then allowed to coolto room temperature. The reaction mixture was diluted with water and theorganics were extracted into dichloromethane. Washing with water, dryingover anhydrous magnesium sulfate and evaporation of solvents resulted ina crude solid which was purified by HPLC using 2:1 hexane/ethyl acetateas the eluent. Recrystallization from acetone yielded 2.5 g of solidwith a melting point of 215°-217° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.12 H.sub.11 ClN.sub.2 O:                                                   61.41% C 4.73% H  11.94% N                                  Found:            61.14% C 4.70% H  11.72% N                                  ______________________________________                                    

EXAMPLE 25 1,2-Dihydro-3-methyl-3H-1,4-oxazino[2,3-c]quinoline

Potassium tertiary butoxide (5 g) was added to a solution of3-bromo-N-(2-hydroxypropyl)-4-quinolinamine (9 g) in 30 ml of DMF andthe mixture stirred at 140° C. for 4 hours. The mixture was cooled toroom temperature and poured into 200 ml of water. The product wasextracted with dichloromethane and purified by HPLC (solvent:DCM:MeOH=10:1).

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.12 H.sub.12 N.sub.2 O.sub.2 :                                             72.00% C 6.00% H   14.00% N                                  Found:           71.99% C 5.87% H   14.10% N                                  ______________________________________                                    

EXAMPLE 26 1,2-Dihydro-3,5-dimethyl-3H-1,4-oxazino[2,3-c]quinoline

A mixture of 18.5 g of3-bromo-N-(2-hydroxypropyl)-2-methyl-4-quinolinamine and 7.0 g ofpotassium tert-butoxide in 100 ml of DMF was stirred at 80°-90° C. for 1hour. The mixture was cooled to room temperature, diluted with 300 ml ofice-water and stirred for 1 hour, whereupon a solid separated which wasfiltered and recrystallized twice from isopropanol and finally fromisopropyl acetate. The yield was 8.7 g, mp 169°-170° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.13 H.sub.14 N.sub.2 O:                                                   72.87% C 6.59% H    13.08% N                                  Found:          72.94% C 6.80% H    13.03% N                                  ______________________________________                                    

EXAMPLE 27 8-Chloro-1,2-dihdyro-3-methyl-3H-1,4-oxazino[2,3-c]quinoline

A solution of 11 g of3-bromo-7-chloro-N-(2-hydroxypropyl)-4-quinolinamine in 33 ml ofdimethylformamide was stirred and to it was added 4.3 g of potassiumt-butoxide. The mixture was stirred at 130°-140° C. for three hours andthen allowed to cool to room temperature. The reaction mixture wasdiluted with water and the organics were extracted into dichloromethane.Washing with water, drying over anhydrous magnesium sulfate andevaporation of solvents resulted in a crude oil which was purified byHPLC using 2:1 hexane/ethyl acetate as the eluent. Recrystallizationfrom acetone yielded 2.5 g of solid with a melting point of 239°-241° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.12 H.sub.11 ClN.sub.2 O:                                                   61.41% C 4.73% H  11.94% N                                  Found:            61.09% C 4.64% H  11.87% N                                  ______________________________________                                    

EXAMPLE 281,2-Dihydro-3-hydroxymethyl-3H-5-methyl-1,4-oxazino[2,3-c]quinoline

A mixture of 3-bromo-N-(2,3-dihydroxypropyl)-2-methyl-4-quinolinamine,potassium tert-butoxide (4 g) and DMF (50 ml) was stirred at 90° C. for4 hours. Thereafter, it was diluted with 500 ml of water and saturatedwith potassium carbonate, and the resultant solid was filtered. Thefiltered liquid was extracted 5 times with dichloromethane. Thedichloromethane-layer was dried over anhydrous magnesium sulfate andconcentrated. The residue and the filtered solid were combined, purifiedby HPLC (DCM:MeOH=10:3) and recrystallized from isopropanol. The yieldwas 2.8 g, mp 197°-199° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.13 H.sub.14 N.sub.2 O.sub.2 :                                             67.81% C 6.13% H   12.17% N                                  Found:           67.72% C 6.08% H   12.02% N                                  ______________________________________                                    

EXAMPLE 29 1,2-Dihydro-3-phenyl-3H-1,4-oxazino[2,3-c]quinoline

Sodium hydride (obtained from 2 g of 50% suspension in mineral oil) wasadded to a solution of3-bromo-N-(2-hydroxy-2-phenylethyl)-4-quinolinamine (10 g) in 50 ml ofDMF and the mixture was stirred at 90° C. for two hours. After coolingto room temperature, it was poured into 250 ml of water and the productextracted with two portions of 100 ml dichloromethane. Thedichloromethane layer was dried over sodium sulfate and concentrated.The oily residue was dissolved in 80 ml of isopropanol, the solution waspoured into 250 ml of ice water and the mixture was stirred for 1 hour.The solid was filtered and recrystallized from isopropanol. The yieldwas 3.1 g, mp 194°-195° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.17 H.sub.14 N.sub.2 O:                                                   77.86% C 5.34% H    10.68% N                                  Found:          77.85% C 5.30% H    10.81% N                                  ______________________________________                                    

EXAMPLE 30 Spiro[cyclohexane-1,3'-[3H][1,4]oxazino[2,3-c]quinoline]

A mixture of 5.5 g of3-bromo-N-(1-hydroxycyclohexylmethyl)-4-quinolinamine, 2.2 g ofpotassium tert-butoxide and 50 ml of DMF was heated at 130° C. for 1hour and then poured into 250 ml of water. The product was extractedwith dichloromethane and ethyl acetate, dried and concentrated, and theresidue was purifed by HPLC using dichloromethane:MeOH=95:5 as theeluent. The fractions containing the product were combined andconcentrated. The residue was taken up in water and stirred for 1 hour,and the solid was filtered and recrystallized from toluene. The yieldwas 2.6 g, mp 164°-165° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.16 H.sub.18 N.sub.2 O:                                                   75.59% C 7.09% H    11.02% N                                  Found:          75.44% C 6.99% H    10.95% N                                  ______________________________________                                    

EXAMPLE 318'-Chloro-spiro[cyclohexane-1,3'-[3H][1,4]oxazino[2,3-c]quinoline]

A solution of 16.4 g of3-bromo-7-chloro-N-[1-hydroxycyclohexylmethyl]-4-quinolinamine in 176 mlof dimethylformamide was stirred at room temperature and to it was added7.54 g of potassium tert-butoxide. The mixture was heated at 130°-140°C. for twenty hours. The reaction mixture was then cooled to roomtemperature, quenched with water, and extracted with an ether/ethylacetate solution. Evaporation of solvents resulted in a crude oil whichwas purified by HPLC using 2:1 hexane/ethyl acetate as the eluent. Asolid resulted which was recrystallized from isopropanol to yield 4 g ofcrystalline solid with a melting point of 216°-218° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.16 H.sub.17 ClN.sub.2 O:                                                   66.54% C 5.94% H  9.70% N                                   Found:            66.26% C 5.89% H  9.42% N                                   ______________________________________                                    

EXAMPLE 32 1-(2-Cyanoethyl)-1,2-dihydro-3H-1,4-oxazino[2,3-c]quinoline

A solution of 2 g of 1,2-dihydro-3H-1,4-oxazino[2,3-c]quinoline, 1.15 gof acrylonitrile, 9.6 g of potassium hydroxide and 0.7 g oftetrabutylammonium bromide in 72 ml of toluene was stirred at roomtemperature for 16 hours. After this time there remained some startingmaterial, therefore, it was necessary to add 50% more acrylonitrile tothe reaction vessel. The mixture was stirred for 5 more hours and thenwashed with water (2×50 ml). Evaporation of solvents resulted in an oilwhich was purified by HPLC using 2:1 ethyl acetate/hexane as the eluent.Rcrystallization from isopropyl acetate gave 2.11 g of solid with amelting point of 104°-107° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.14 H.sub.13 N.sub.3 O:                                                   70.28% C 5.48% H    17.56% N                                  Found:          69.99% C 5.31% H    17.29% N                                  ______________________________________                                    

We claim:
 1. A compound of the formula ##STR11## where X is hydrogen,loweralkyl, loweralkoxy, hydroxy, halogen, nitro or trifluoromethyl; R₁is hydrogen or loweralkyl; R₃ and R₄ are independently hydrogen orloweralkyl; R₅ +R₆ taken together with the carbon atom to which they areattached constitute a cyclopropane, cyclobutane, cyclopentane, orcyclohexane ring, and R₉ is hydrogen or bromine, the term loweralkyl ineach occurrence signifying a straight or branched alkyl group havingfrom 1 to 6 carbon atoms and the term loweralkoxy signifying a straightor branched alkoxy group having from 1 to 6 carbon atoms, or apharmaceutically acceptable acid addition salt thereof.
 2. The compoundas defined in claim 1, where R₁ is hydrogen or methyl.
 3. The compoundas defined in claim 1, where X is hydrogen or halogen.
 4. The compoundas defined in claim 1, where R₉ is hydrogen.
 5. The compound as definedin claim 1, where R₉ is bromine.
 6. The compound as defined in claim 4,where R₅ and R₆ taken together with the carbon atom to which they areattached constitute a cyclohexyl ring.
 7. The compound as defined inclaim 5, where R₅ and R₆ taken together with the carbon atom to whichthey are attached constitute a cyclohexyl ring.
 8. The compound asdefined in claim 1, which is7-chloro-N-[(1-hydroxycyclohexyl)methyl]-4-quinolinamine.
 9. Thecompound as defined in claim 7, which is3-bromo-N[(1-hydroxycyclohexyl)methyl]-4-quinolinamine.
 10. The compoundas defined in claim 7, which is3-bromo-7-chloro-N-[(1-hydroxycyclohexyl)methyl]-4-quinolinamine.
 11. Apharmaceutical composition comprising an effective memory enhancingamount of a compound as defined in claim 1 and a suitable carriertherefor.
 12. A method of treating a patient in need of memoryenhancement which comprises administration of an effective memoryenhancing amount of a compound as defined in claim 1.